DESCRIPTION: Cataracts are the leading cause of blindness in the world. To date, there are no non-surgical methods to prevent or delay cataract formation. It is generally accepted that cataracts can be caused by dysfunctional lens proteins, including connexins and crystallins, resulting from age-related changes, environmental risk factors, predisposed genetic defects or diseases, such as diabetes. However, the regulation of lens homeostasis required for the maintenance of lens transparency and the early events of cataractogenesis remain poorly understood. The majority of human hereditary cataracts are linked to mutations of crystallin and connexin genes. The overall objective of our proposal is to elucidate how connexins and crystallins regulate lens transparency and cataractogenesis. The long-term goal of our research is to develop novel therapeutics for delaying cataract formation. Our recent findings show that the combination of connexin point mutations with endogenous wild type connexins disrupts lens fiber cell formation to cause cataracts. Knockin alpha3 connexin prevents cataracts caused by connexin or gamma-crystallin gene mutations. We hypothesize that 1) by interacting with wild type connexins, mutant connexins uniquely alter gap junction channel permeability to disrupt lens primary or secondary fiber cell formation, ultimately leading to different types of cataracts;2) knockin alpha3 connexin restores the stability and/or solubility of gamma-crystallin proteins to rescue dense nuclear cataracts;3) the variability of cataracts in connexin mutant mice is caused by predisposed genetic modifiers. Proposed studies are organized in three specific aims for evaluating these hypotheses. Aim 1: Determine if changes in gap junction permeability affect the formation of lens primary or secondary fiber cells in alpha8 connexin mutant mice. Aim 2: Determine if knockin alpha3 connexin rescues nuclear cataracts in gammaB-crystallin mutant mice by restoring the stability and/or solubility of mutant gammaB-crystallin proteins. Aim 3: Identify genetic modifiers that influence lens phenotypes in connexin mutant mice. These studies will shed new mechanistic insights on the roles of gap junction communication in cataract formation and prevention.